About

Charles A. Stanley, M.D., is an Emeritus Professor and Chief of Pediatrics (Endocrinology and Diabetes) at the University of Pennsylvania's Perelman School of Medicine. He is also a Senior Physician specializing in Endocrine and Diabetes at the Children's Hospital of Philadelphia. His research expertise focuses on genetic disorders of carbohydrate and fatty acid metabolism, insulin secretion, hypoglycemia, glycogenoses, fatty acid oxidation disorders, and diabetes mellitus. Dr. Stanley has contributed to understanding the mechanisms of insulin secretion, hyperinsulinism, and related metabolic disorders, with numerous publications advancing the field of pediatric endocrinology.

Research topics

• Medicine
• Internal medicine
• Endocrinology
• Biology
• Pediatrics

Selected publications

• Supplemental data from: Determinants of hyperinsulinism severity in children with Beckwith-Wiedemann Syndrome

  Open MIND · 2026-01-08

  dataset

  Context: Congenital hyperinsulinism (HI) is a serious clinical feature of Beckwith-Wiedemann syndrome (BWS) causing severe hypoglycemia. The relationship between BWS genotypes and HI severity is not well understood. Objective: Investigate the relationship between molecular determinants of patients with BWS and HI with measures of HI severity. Design: Retrospective cohort study including 85 children from 2009-2024. Setting: All patients evaluated at single, tertiary care center. Patients: BWS genotype frequency included 41 children with pUPD11, 24 with IC2 LOM, eight with 11p15 chromosomal anomalies, six with GWpUPD, four with IC1 GOM, and two with CDKN1C. Interventions: Retrospectively reviewed interventions included maximum glucose infusion rate (max GIR), diazoxide responsiveness, and surgery. Main Outcome Measures: Primary outcome was association between BWS genotypes and measures of HI severity. Secondary outcomes included the relationship between pUPD11 length and presence of K-ATP variants with diazoxide responsiveness and surgical need. Results: Significant differences presented among genotypes in max GIR (p = 0.004), enteral dextrose requirements (p = 0.029), and pancreatectomy (p = 0.012). Most patients with IC2 LOM, IC1 GOM or CDKN1C were diazoxide responsive and did not require surgery. Patients with pUPD11 were more likely to be diazoxide unresponsive and require surgery, especially if pUPD11 length extended into the K-ATP gene region and if a pathogenic variant in the ABCC8 or KCNJ11 was present. Conclusion: Patients with pUPD11 experience more severe HI, while patients with IC2 LOM, IC1 GOM, and CDKN1C exhibit milder disease. Based on our findings, we designed a genetic testing algorithm to guide clinical management.

  DOI

• Determinants of hyperinsulinism severity in children with Beckwith-Wiedemann syndrome

  The Journal of Clinical Endocrinology & Metabolism · 2026-02-06 · 1 citations

  article

  CONTEXT: Congenital hyperinsulinism (HI) is a serious clinical feature of Beckwith-Wiedemann syndrome (BWS) causing severe hypoglycemia. The relationship between BWS genotypes and HI severity is not well understood. OBJECTIVE: Investigate the relationship between molecular determinants of patients with BWS and HI with measures of HI severity. DESIGN: Retrospective cohort study including 85 children from 2009-2024. SETTING: All patients evaluated at single, tertiary care center. PATIENTS: BWS genotype frequency included 41 children with pUPD11, 24 with IC2 LOM, eight with 11p15 chromosomal anomalies, six with GWpUPD, four with IC1 GOM, and two with CDKN1C. INTERVENTIONS: Retrospectively reviewed interventions included maximum glucose infusion rate (max GIR), diazoxide responsiveness, and surgery. MAIN OUTCOME MEASURES: Primary outcome was association between BWS genotypes and measures of HI severity. Secondary outcomes included the relationship between pUPD11 length and presence of K-ATP variants with diazoxide responsiveness and surgical need. RESULTS: Significant differences presented among genotypes in max GIR (p = 0.004), enteral dextrose requirements (p = 0.029), and pancreatectomy (p = 0.012). Most patients with IC2 LOM, IC1 GOM or CDKN1C were diazoxide responsive and did not require surgery. Patients with pUPD11 were more likely to be diazoxide unresponsive and require surgery, especially if pUPD11 length extended into the K-ATP gene region and if a pathogenic variant in the ABCC8 or KCNJ11 was present. CONCLUSION: Patients with pUPD11 experience more severe HI, while patients with IC2 LOM, IC1 GOM, and CDKN1C exhibit milder disease. Based on our findings, we designed a genetic testing algorithm to guide clinical management.

  PublisherDOI

• Noncoding Variants in Intron 2 of <i>HK1</i> Associated With Hyperinsulinism With Variable Clinical Phenotype

  The Journal of Clinical Endocrinology & Metabolism · 2026-03-07

  articleOpen access

  INTRODUCTION: Non-coding variants in HK1 were first associated with congenital hyperinsulinism (HI) in a large family with diazoxide-responsive HI in 2008. Since then, additional cases have been reported in the literature with non-coding variants in HK1 associated with variable HI phenotypes. METHODS: We sequenced a 350bp region in intron 2 of HK1 in 281 individuals with genetics negative HI to identify additional cases related to non-coding HK1 variants and to characterize the clinical features of these cases. RESULTS: We identified 16 unique non-coding variants in intron 2 of HK1 in 18 individuals with genetics negative HI (18/281, 6.4%). In seven cases (7/18, 39%), the HK1 variant was inherited from a parent (2 maternal, 5 paternal), two are known to be affected with HI. In nine cases, the HK1 variant was de novo (9/18, 50%). The age of presentation of HI ranged from day of life one to 21 months of age. Seven cases had diazoxide-responsive HI (7/18, 39%). Eleven cases were diazoxide unresponsive (11/18, 61%); five underwent pancreatectomy at ages ranging from six months to three years of age. CONCLUSIONS: Non-coding variants in intron 2 of the HK1 gene have now been associated with HI in a growing number of cases. Our findings suggest that a significant proportion of individuals with negative genetics in genes currently known to be associated with HI may harbor HK1 intron 2 variants. Identifying these cases is important for clinical care as well as for assessing recurrence risk for families.

  PublisherDOI

• Congenital Hyperinsulinism and Long QT Syndrome Attributable to a Variant in KCNE1

  Hormone Research in Paediatrics · 2025-01-08 · 1 citations

  articleOpen access

  INTRODUCTION: This is a report of a child with congenital hyperinsulinism associated with a loss-of-function variant in KCNE1. KCNE1 encodes a human potassium channel accessory (beta) subunit that modulates potassium channel Kv7.1 (encoded by KCNQ1). Loss-of-function pathogenic variants in either the KCNQ1 or KCNE1 genes result in long QT syndrome by causing prolongation in the action potential duration at the cellular level. In addition to long QT syndrome, the phenotype associated with loss-of-function pathogenic variants in KCNQ1 is characterized by postprandial hyperinsulinemic hypoglycemia. CASE PRESENTATION: Clinical data for the proband were extracted from the medical records. The proband presented with fasting hypoglycemia due to hyperinsulinism in early childhood as well as postprandial hypoglycemia triggered by carbohydrates and by protein. Whole-exome sequencing was undertaken in genomic DNA isolated from proband and both parents. Whole-exome sequencing revealed a variant in KCNE1 inherited from the father, who also has a history of hyperinsulinism. Both the patient and father were subsequently diagnosed with long QT syndrome. The proband and father underwent phenotype testing including fasting test, oral glucose tolerance test, oral protein tolerance test, and exercise tolerance test. CONCLUSIONS: This case illustrates that loss-of-function variants in KCNE1, similar to KCNQ1, are associated with a cardiac and a beta cell phenotype, and thus, this patient population should be screened for hypoglycemia, particularly in the postprandial state.

  PublisherOA PDFDOI

• Developing a congenital hyperinsulinism prioritized research agenda: a patient-driven international collaborative research network

  Frontiers in Endocrinology · 2025-05-02 · 2 citations

  articleOpen access

  Introduction: Congenital Hyperinsulinism (HI) is a rare disease that causes severe and recurrent hypoglycemia due to dysregulated insulin secretion. HI is the most frequent cause of severe, persistent hypoglycemia in newborns and children. Disease management is focused on preventing the neurological consequences associated with hypoglycemic brain injury; however, treatment is complex, often suboptimal, and places a large burden on families and individuals living with HI. Congenital Hyperinsulinism International (CHI) is an international patient organization that received a grant from the Chan Zuckerberg Initiative to establish the CHI Collaborative Research Network (CRN), a collaborative body to accelerate research for HI. Assessment process: Stakeholder groups relevant to HI, including individuals living with HI, families, researchers, clinicians, nurses, and industry partners, were identified to join the CRN and work together to create a prioritized research agenda (PRA) to systematically rank research priorities. CRN members worked across 7 workstream groups through a structured process to brainstorm gaps and corresponding solutions to formalize the HI PRA. Actionable recommendations: A total of 362 gaps were identified across research, infrastructure, knowledge, and funding. All groups identified the need for an HI Natural History Study; therefore, this item was identified as a priority that would automatically be placed on the finalized list. Other top gaps identified in the PRA addressed preventing brain damage and the need to increase awareness and understanding related to the role of early and effective diagnosis in preventing brain damage. Discussion: The formation of the CRN and the development of the PRA have already led to new collaborations, which are fundamental to progress. The PRA process allowed individuals to come to a consensus on the critical needs and to chart short- and long-term approaches to fill the gaps. CRN members continue to meet regularly in working groups focused on special projects to fill gaps identified as high priority by the PRA. Through this active and multidimensional alliance, the CRN is re-imagining the future for people living with HI by improving outcomes through more timely and accurate diagnosis, more effective and less burdensome treatments, more easily obtainable expert care, and better tools to manage HI.

  PublisherOA PDFDOI

• Identification and Rescue of Congenital Hyperinsulinism-Associated <i>ABCC8</i> Mutations that Impair K _ATP Channel Trafficking

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-19

  preprintOpen access

  Abstract ATP-sensitive potassium (K ATP ) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) couple glucose metabolism with insulin secretion in pancreatic β-cells and are vital to glucose homeostasis. Loss-of-function mutations in SUR1 and Kir6.2, encoded by ABCC8 and KCNJ11 , respectively are the commonest causes of severe persistent hypoglycemia in infants and children seen in the rare disease congenital hyperinsulinism (HI). The N-terminal transmembrane domain, TMD0, and the linker immediately C-terminal to TMD0, L0, of SUR1 (TMD0/L0) forms direct contact with Kir6.2 in K ATP channels. Mutations in SUR1-TMD0 often impair K ATP channel trafficking to the plasma membrane, causing severe disease unresponsive to treatment by the K ATP activator diazoxide; however, surface expression and function of many such mutant channels can be rescued by reversible K ATP inhibitor pharmacochaperones. Here, we identified seven new SUR1 missense mutations in TMD0/L0 from HI patients unresponsive to diazoxide and investigated their effects on K ATP channel expression, function, and response to pharmacochaperones. All seven mutations, N32K, Y124F, P133R, W143R, L171P, G228D, and Y230C, reduced channel function in Rb + efflux assays. Further characterization by immunoblotting, immunostaining and electrophysiology revealed that Y124F primarily causes defective channel gating, while the others impair channel trafficking to different extents. The trafficking mutations showed varied response to surface expression and function rescue by the reversible K ATP inhibitor pharmacochaperones, tolbutamide and Aekatperone. The study underscores the critical role of SUR1-TMD0/L0 in K ATP expression and gating. It further highlights the importance of detailed biochemical and functional studies of mutant channels in understanding their pathogenic roles and response to potential pharmacological therapies.

  PublisherOA PDFDOI

• Identification and rescue of congenital hyperinsulinism-associated ABCC8 mutations that impair KATP channel trafficking

  Journal of Biological Chemistry · 2025-09-27 · 1 citations

  articleOpen access

  expression and gating. It further highlights the importance of detailed biochemical and functional studies of mutant channels in understanding their pathogenic roles and response to potential pharmacological therapies.

  PublisherOA PDFDOI

• Role of beta-hydroxybutyrate measurement in the evaluation of plasma glucose concentrations in newborn infants

  Archives of Disease in Childhood Fetal & Neonatal · 2024-03-01 · 6 citations

  articleOpen access1st author

  OBJECTIVE: The Glucose in Well Babies (GLOW) Study showed that there are two phases of low glucose concentrations in healthy newborn infants: an initial phase in which plasma concentrations of ketones are low; and a second phase in which low glucose concentrations are accompanied by elevated concentrations of ketones. The implications of these two phases for the brain differ depending on whether ketones are available as alternative substrate for brain metabolism. The purpose of this study was to estimate the duration of these two phases of neonatal low glucose concentrations in 66 healthy breastfed newborns from the GLOW Study during the first 5 days of life. METHODS: The sum of glucose and beta-hydroxybutyrate (BOHB) was used as a proxy for the total concentrations of insulin-dependent fuels for the brain; a threshold value below 4 mmol/L was taken to indicate the presence of relative hyperinsulinism and a BOHB concentration above 0.5 mmol/L to indicate ketonaemia. RESULTS: The first phase of low glucose concentrations lasted a median of 40 hours and in 15% of infants, this persisted beyond 60 hours. Fifty (76%) of the 66 infants subsequently had ketonaemia, which resolved at a median age of 76 hours (range 41->120 hours). CONCLUSIONS: These data suggest that monitoring BOHB concentrations may be useful for interpreting glucose concentrations in newborns and screening for persistent hyperinsulinism.

  PublisherOA PDFDOI

• Hypoglycemia

  Pediatric Endocrinology · 2024-01-01

  book-chapterOpen accessSenior author

  Hypoglycemia is a medical emergency that may result in seizures, permanent brain damage, or even sudden death. Because hypoglycemia can be the presenting sign of a large list of pathologies, it is necessary to have a comprehensive strategy for diagnosis. An approach based on the metabolic and endocrine systems involved in successful adaptation to fasting leads to timely diagnosis and treatment of hypoglycemia disorders. Suspected hypoglycemia should be evaluated through a closely monitored fasting test to obtain a critical sample when the plasma glucose is less than 50 mg/dL. To minimize the risk of neurologic damage, the therapeutic goal for children with hypoglycemic disorders is to maintain plasma glucoses above 70 mg/dL while encouraging normal feeding behavior.

  PublisherDOI

• Low-Level Mosaic <i>GCK</i> Mutations in Children With Diazoxide-Unresponsive Congenital Hyperinsulinism

  The Journal of Clinical Endocrinology & Metabolism · 2024-10-08 · 5 citations

  articleOpen access

  CONTEXT: Some children with diazoxide-unresponsive congenital hyperinsulinism (HI) lack any detectable disease-causing mutation in peripheral-blood DNA. OBJECTIVE: This work aimed to examine whether somatic postzygotic mutations of known HI genes are responsible for disease in children with diazoxide-unresponsive HI requiring surgery with histology not classified as focal or localized islet nuclear enlargement (LINE), and without detectable mutations by standard genetic testing of peripheral blood DNA. METHODS: Next-generation sequencing (NGS) was performed on specimens of pancreas from 10 children with diazoxide-unresponsive HI. RESULTS: Four unique GCK mutations were identified at low levels of mosaicism ranging from 4.4% to 10.1% in pancreatic DNA from 5 of these 10 children. The GCK mutations were not detectable in peripheral-blood DNA by NGS in 3 cases from which peripheral-blood DNA was available for testing. All 4 GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse HI in 4 of the 5 cases with mosaic GCK mutations. In one of these, hypomethylation of IC2 on chromosome 11p was identified in pancreatic and peripheral-blood DNA. Histology of the fifth case revealed minor islet abnormalities suggestive of Beckwith-Wiedemann spectrum although molecular analysis for 11pUPD was negative in pancreas. CONCLUSION: These results indicate that postzygotic somatic GCK mutations are responsible for some cases of nonfocal diazoxide-unresponsive HI.

  PublisherDOI

Recent grants

• NIH Grant R01DK043841

  NIH · $863k · 1998

• NIH Grant M01RR000240

  NIH · $6.4M · 2006

• NIH Grant K12DK063682

  NIH · $1.4M · 2009

• NIH Grant S10RR026853

  NIH · $150k · 2011

• NIH Grant R01DK053012

  NIH · $5.0M · 2013

Frequent coauthors

• Diva D. De León

  Children's Hospital of Philadelphia

  152 shared

• Paul Thornton

  Cook Children's Medical Center

  102 shared

• Andrea Kelly

  Children's Hospital of Philadelphia

  101 shared

• N. Scott Adzick

  University of Pennsylvania

  87 shared

• Lester Baker

  Children's Hospital of Philadelphia

  84 shared

• Betty Y.L. Hsu

  68 shared

• Changhong Li

  State Key Laboratory of Food Science and Technology

  60 shared

• Arupa Ganguly

  University of Pennsylvania

  56 shared

Labs

• Charles A. Stanley LaboratoryPI